In our initial grant, we proposed to optimize intraperitoneal PDT to deal with tumors involving the peritoneal surface. We showed that IP-PDT to the peritoneum was feasible and tolerable, with acceptable toxicity but marginal efficacy. We demonstrated that IP-PDT has a narrow therapeutic ratio reflecting relatively poor ratios of tumor to normal tissue retention of Photofrin. In this renewal, we will study the biological and molecular enhancement of the PDT process by blocking EGF receptor. Preclinical studies show EGFR blockade in combination with PDT improves cytoxicity without increasing normal tissue toxicity. This suggests that inhibiting signal transduction after PDT can improve the therapeutic index of IP-PDT and yield more efficacy without toxicity. In Project 1, we will optimize IP-PDT by using a second generation photosensitizer (BPD) in combination with cetuximab to alter signal transduction in human tumors and thus enhance the therapeutic index of IP-PDT. Project 2 aims to optimize serosal PDT by inhibiting relevant components of signal transduction pathways. This project will define the impact of inhibiting EGF signaling on cytotoxicity and mechanisms of cell death following BPD mediated PDT of ovarian and lung cancer cells. We will use small molecules/antibody inhibitors and siRNA to inhibit EGF receptor and post-receptor signaling pathways. We will study both sequence and timing of PDT and growth factor pathway inhibition to maximize this synergistic effect. Project 3 will study the microenvironmental effects of PDT combined with targeted molecular therapy. We will define the relationship between tumor microenvironment and PDT outcome, with specific attention to the AKT signal transduction pathway looking at Avastin, C225 and nelfinavir. In Project 4, we will look at real-time optical diagnostics of tissue for PDT dosimetry and treatment with major emphasis on characterizing tumor microenvironment brought about by biological targeting while assessing our dosimetry. We have added a new Project 5, of IP-PDT for lung cancer presenting with pleural carcinomatosis. This work has gone on in parallel with our grant but not funded. Our clinical results appear to validate the concept of PDT for treatment of surface malignancies. This program project grant is largely translational and offers a novel and potentially effective therapy for cancers involving serosal surfaces.